The invention relates to basic acetophenones as inhibitors of NO-synthases and their use for producing medicaments.
NO-synthases (NOS) catalyze the reaction of the amino acid L-arginine to nitrogen monoxide (NO) and L-citrullin. Due to the participation of a surplus production of nitrogen monoxide in numerous pathophysiological processes (Stuehr., 1999, Biochim Biophys Acta, 1411, 217-230), the development of NO-synthase inhibitors is looked upon as a very promising strategy (Babu and Griffith, 1998, Curr Opin Chem Biol, 2, 491-500). A reinforcing action on the pathological processes of excessively produced nitrogen monoxide e.g. occurs with Alzheimer's disease (Dorheim et al., 1994, Biochem Biophys Res Commun, 205, 659-665), pancreatic diabetes (Li and Förstermann, 2000, J. Pathol, 190, 244-254), Parkinson's disease (Schulz et al., 1995, J. Neurochem, 64, 936-939), multiple sclerosis (Heales et al., 1999, Biochim Biophys Acta, 1410, 215-228), rheumatoid arthritis (Stefanovic-Racic et al., 1993, Arthritis Rheum, 36, 1036-1046), septicemic shock (Crossin, 1991, Trends Biochim Sci, 1991, 16, 81-82), bronchial asthma (Ligget et al., 1995, Am J Respir Crit Care Med, 152, 394-402), chronic inflammatory intestinal diseases (Boughton-Smith et al., 1993, Lancet, 342, 338-340), and migraine (Olesen et al., 1994, Trends Pharmacol Sci, 15, 149-153). Against this background over the last few years numerous inhibitors have been developed, which in part have proved effective in animal models for the indicated diseases. Particular promise is shown by the pharmacological blocking of NO-synthases of those pain processes involving an inflammatory component. In the animal model NOS inhibitors here act both on the nociceptor plane and on the transmission plane (Stegmann et al., 2001, Anasthesiol Intensivmed Notfallmed Schmerzther, 36, 276-281). Unfortunately up to now it has not been possible to develop any of said inhibitors to provide a medicament (Roman et al., 2002, Chem Rev, 102, 1179-1189).
Therefore the problem of the present invention is to provide compounds which in particular act as inhibitors for NO-synthases and which are suitable as pharmaceutical substances in medicaments.